The Broad Institute, Inc.

The General Hospital Corporation

Dana-farber-cancer Institute Inc.

Harvard College

The Board Institute, Inc.

Alykhan Shamji

Ramnik Xavier

Thomas Sundberg

Nathanael Schiander Gray

Yanke Liang

Stuart L Schreiber

Hwan Geun Choi

David E Fisher

Nisma Mujahid

Benito Munoz

Henry M Kronenberg

Andrew Stern

Daisuke Ito

Ke Liu

Matthias Leiendecker

Jason Law

Mahmud Hussain

Marc Wein

Nathanael S Gray

Jose R Perez

Daniel B Graham

Bernard Khor

Liv Johannessen

Michael Durney

Jason Rush

Zhifang Cao

Elizaveta Leshchiner

The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.

Bicyclic urea kinase inhibitors and uses thereof

The present disclosure provides methods of treating and/or preventing osteoporosis using salt-inducible kinase (SIK) inhibitors. Also provided are methods of using SIK inhibitors for increasing the function of osteocytes, increasing the number of osteoblasts, increasing the activity of osteoblasts, inhibiting the resorption of a bone, decreasing the number of osteoclasts, inhibiting the activity of osteoclasts, increasing the mass of a bone, down-regulating the expression of the gene SOST, and/or inhibiting the activity of sclerostin. The SIK inhibitors may be combined with Src inhibitors or CSF1R inhibitors. Exemplary SIK inhibitors include the compounds of the formula:

Uses of salt-inducible kinase (SIK) inhibitors for treating osteoporosis

Disclosed herein are compounds for the treatment of inflammatory bowel disease. Additionally, provided herein are compositions and methods for using these compounds and compositions in the treatment of inflammatory bowel disease in a subject.

Compositions and methods for treating inflammatory bowel disease

A method for treating inflammation and/or autoimmune diseases comprises administering to a subject in need thereof, a composition comprising a CDK8 inhibitor. In another aspect, a method for increasing IL-10 production comprises administering to a subject in need thereof a CDK8 inhibitor. In another aspect, a method for enhancing Tcell differentiation, comprising administering a composition comprising a CDK8 inhibitor. In certain example embodiments, the subject suffers from an inflammatory bowel disease. In certain other example embodiments, the subject requires immunosuppression to prevent rejection following a transplantation procedure.

Use of CDK8 inhibitors to treat diseases of inflammation and autoimmunity

The present disclosure provides methods of treating and/or preventing osteoporosis using salt-inducible kinase (SIK) inhibitors. Also provided are methods of using SIK inhibitors for increasing the function of osteocytes, increasing the number of osteoblasts, increasing the activity of osteoblasts, inhibiting the resorption of a bone, decreasing the number of osteoclasts, inhibiting the activity of osteoclasts, increasing the mass of a bone, down-regulating the expression of the gene SOST, and/or inhibiting the activity of sclerostin. The SIK inhibitors may be combined with Src inhibitors or CSF I R inhibitors. Exemplary SIK inhibitors include the compounds of the formula: (I), (II), (III), (IV), (V) or (VI). 

The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein. 

The present disclosure provides methods of treating and/or preventing inflammatory bowel disease (IBD) and graft-versus-host disease (GVHD) using salt-inducible kinase (SIK) inhibitors, such as macrocyclic SIK inhibitors of Formula (I), imidazolyl SIK inhibitors of Formula (II), and urea and carbamate SIK inhibitors of Formula (III-A) (e.g., urea and carbamate SIK inhibitors of Formula (III)). 

Uses of salt-inducible kinase (SIK) inhibitors

The invention relates to compounds of Formula I or a pharmaceutically acceptable salt, ester or prodrug thereof: 

Compounds and methods for the treatment of isocitrate dehydrogenase related diseases

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Somerville, MA, United States of America

Alykhan Shamji